Glial Growth Factors I-III Are Specific Mitogens for Glial Cells

Recently we identified three novel Schwann cell mitogens named GGF (glial growth factor)-I (34 kDa), GGF-II (59 kDa), and GGF-III (45 kDa), and provided evidence that they are three distinct but structurally related members of a larger family of factors, which includes heregulin, neu differentiation factor, and acetylcholine receptor-inducing activity (ARIA). We report here the characterization of the mitogenic and trophic activities for all three forms of GGF on rat Schwann cells and several other cell types. GGF-I, GGF-II, and GGF-III are potent mitogens for rat Schwann cells in vitro at nanomolar concentrations, whereas at lower concentrations they promote Schwann cell survival, in the absence of cAMP elevating agents. Forskolin, an adenylate cyclase activator, potently synergizes with the GGFs by an indirect mechanism, possibly involving transcriptional activation of GGF receptor(s). In addition, the GGFs stimulate DNA synthesis in rat glioma C6 cells, and in SK-BR-3 cells, which overexpress the p185 neu/erbB2. Fibroblasts obtained from different sources are weakly stimulated by GGFs, whereas PC12 cells are unable to respond under a variety of experimental conditions. These observations are consistent with the proposal that GGF-I, GGF-II, and GGF-III are a set of potent glial cell mitogens and putative ligands of members of the EGF receptor family, namely p185 neu/erbB2, p160/erbB3, and p180/erbB4, which may play important roles in the development, regeneration, and tumor biology of the peripheral nervous system.